Congestive heart failure (CHF) is a major cause of death in patients with heart disease. Digitalis glycosides (Drug that is extracted from the leaves of the foxglove plant) have been used for the treatment of CHF for more than 200 years (Gheorghiade, M.; Zarowitz, B. J.; Am. J. Cardiol., 1992, 69, 48G). However, application of these agents are limited because of their narrow therapeutic window and their propensity that cause life-threatening arrhythmias (arrhythmogenic liability). Thus digitalis has been replaced by a new class of cardiotonic agents named as a well known PDE3 inhibitor Amrinonei and Milrinone, a 2-oxopyridine derivative that has been introduced to the clinic for the treatment of CHF in place of digitalis (Kikura, M.; Levy, J. H.; Int. Anestesiol. Clin., 1995, 33, 21). These PDE inhibitors display a greater safety profile and improved efficacy on patient survival.
Phosphodiesterases are a class of intracellular enzymes responsible for the hydrolysis of cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP) which are involved in the regulation of important cell functions, such as secretion, contraction, metabolism, and growth (Potter, B. V. L.; Transmembrane Signalling Second Messenger Analogues and Inositol Phosphates. In Comprehensive Medical Chemistry; Hansch, C.; Sammes, P. G.; Taylor, J. B., Eds. Pergamon Press: Oxford, 1990; pp 102-128). On the basis of structure, and substrate specificity PDE enzymes can be grouped into eleven different families, PDE1 to PDE11 (Beavo, J. A.; Physiol. Rev., 1995, 75, 725).
Each PDE isozyme has a conserved C-terminal catalytic domain and unique N-terminal regulatory domain. These isozymes are found in different tissues and cells of the humans such as smooth muscle, brain, heart, lung, platelets, lymphocytes etc. and in other species (Bender, A. T.; Beavo, J. A.; Pharmacol Rev., 2006, 58, 488). PDE3 and PDE4 are well established in cardiovascular tissues (Nicholson, C. D.; Challiss, R. A. J.; Shahid, M.; Trends Phahrmacol Sci., 1991, 12, 19). Among all subtypes of PDE, PDE3 is predominantly expressed in heart and platelets. Thus PDE3 play an important role in heart and platelet (Palson, J. B.; Strada, S. J.; Annu. Rev. Pharmacol. Toxicol., 1996, 36, 403).
Inhibition of PDE brings about various physiological reactions, for example inhibition of PDE3 enhances myocardial contraction, produces vasodilatation, and suppresses platelet aggregation (Abadi, A. H.; Ibrahim, T. M.; Abouzid, K. M.; Lehmann, J.; Tinsley, H. N.; Gary, B. D.; Piazza, G. A.; Bioorg. Med. Chem. 2009, 17, 5974). These are the reasons why PDE3 inhibitors can be used to treat heart failure.
In addition, the PDE3 isozyme is specific for c-AMP and has no effect on c-GMP and calmodulin. Therefore, inhibition of PDE3 isoenzyme in cardiovascular tissues may lead to high levels of c-AMP and consequent inotropic effect.
Recent studies revealing that PDE3, PDE4, and PDE5 isozymes are over expressed in cancerous cells compared with normal cells. Thus inhibition of PDE3 together with other PDE's may lead to inhibition of tumor cell growth and angiogenesis (Cheng, J. B. and Grande, J. P.; Exp. Biol. Med., 2007, 232, 38).
Recently, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease (COPD). PDE4 or PDE3 inhibitors alone are unable to inhibit spasmogen-induced contraction of human airway, but in combination act synergistically. While PDE3 inhibitor has been shown to inhibit cough, PDE4 inhibitor may be able to stimulate mucociliary clearance. This diverse spectrum of biological effects has thus implicated PDE3/4 inhibitors as potential therapeutic agents for a range of disease indications including COPD. (Banner, K. H.; Press, N.J.; Br. J. Pharmacol., 2009, 157(6): 892-906.)
The present invention describes the synthesis of novel pyridopyrimidine based derivatives as inhibitors of phosphodiesterase3 (PDE3). PDE3 inhibitors are useful for the prevention of heart failure and inhibit platelet aggregation.
The following references are examples for the synthesis and biological evaluation of some of the PDE or PDE3 inhibitors. The prior art contain useful information and discussion on the preparation and properties of PDE inhibitors.
U.S. Pat. No. 5,141,931, reported synthesis of 6-Alkyl-5-(6, or 7-quinolinyl)-3-(substituted)-2(1H)-pyridinones which are useful as cardiotonics. Inhibition of PDE3 was reported to have cardiotonic effect of these compounds.
U.S. Pat. No. 10,151,202, reports novel pyrrolidine compounds that are potent and selective inhibitors of PDE 4, as well as methods development for the synthesis of novel molecules.
Recently our publication reported [Ravinder et al Bioorg. Med. Chem. Lett., (2012)] Synthesis and Evaluation of Novel 2-Pyridone Derivatives as Inhibitors of Phospho-diestarase3 (PDE3): A Target for Heart Failure and Platelet Aggregation.
Ochiai et al., Bioorg Med. Chem., 20(5):1644-1658 (2012) reported synthesis of (−)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H) pyridazinone (KCA-1490), a dual PDE 3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity.

FIG. 1 Phosphorodiesterase3 (PDE3) inhibitors